Prevention of benznidazole-induced prolonging effect on the pentobarbital sleeping time of rats using different thiol-containing compounds

Benznidazole (BZ) is a nitroimidazolic chemotherapeutic agent employed agai nst the acute and indeterminate phase of Chagas' disease, a tropical sickne ss afflicting more than twenty million people in Latin America. BZ has seri ous toxic side effects forcing people to stop treatment. These effects were attributed to the nitroreductive metabolic activation of BZ to a hydronitr oxide radical or the hydroxylamine, which would covalently bind to cellular components. One of these deleterious effects is the prolongation on the pe ntobarbital sleeping time of rats. This results from the covalent binding o f BZ reactive metabolites, arisen during its nitroreductive metabolism, to the phospholipid component of the mixed function oxidase which biotransform the barbiturate. In this study, the potential ability of different thiol containing drugs to trap BZ reactive metabolites and to prevent BZ effect on the pentobarbital sleeping time was tested. Our HPLC studies evidenced that cysteine, N-acet ylcysteine, penicillamine and glutathione were able to trap BZ reactive met abolites in vitro to produce one or two adducts. Reduced lipoic acid instea d, decreased the intensity of the nitroreductive process without leading to detectable adducts. The in vivo administration of the thiol drags, at dosa ge regimes available in literature, was able to markedly prevent the BZ pro longation effect on the sleeping time. Whether these thiols might prevent o ther BZ toxic effects without harming its chemotherapeutic actions remains to be established.